Hippocampal neurogenesis and remodeling

早期生活中的应激经历与下丘脑-垂体-肾上腺(HPA)轴的异常、行为变化和精神病理学的发展有关。研究大脑对发育应激源的反应所发生的细胞变化，可能会让我们更接近理解这些功能后果背后的机制。该中心拨款提案中的其他项目旨在从分子到行为的不同分析水平上探索压力诱导的大脑变化。这个项目将研究早年厌恶经历对大脑结构的影响。这里提出的研究重点是海马区，这是一个对压力敏感的区域，与包括抑郁症和创伤后应激障碍在内的精神病理有关。海马区在出生后经历了广泛的发展，这可能使这一结构潜在地容易受到环境扰动的影响。特别是齿状回的颗粒神经元主要形成于出生后时期。事实上，在从啮齿动物到灵长类动物的大多数哺乳动物中，这些细胞的产生一直延伸到成年。此前的研究表明，这些海马神经元的产生在成年后会受到压力的抑制。本研究旨在利用CORE(PI，Plotsky)，(PI，Insel)提供的啮齿动物和灵长类动物模型，探讨长时间的早期生活应激对颗粒神经元群体、CA3锥体神经元群体的发育以及这两个细胞群体之间苔藓纤维联系的影响。采用BrdU标记、~3H-胸腺嘧啶核苷放射自显影、免疫细胞化学、高尔基体染色和神经解剖束示踪等多种组织学方法，探讨早期生活应激对海马神经元形成和维持的影响。这些研究将有助于该中心的总体目标，以更好地了解早期生活应激对大脑结构和功能的影响，并最终有助于发展精神病理学。

Stressful experiences during early life have been associated with abnormalities in the hypothalamicpituitary-adrenal (HPA) axis, changes in behavior and the development of psychopathology. Studying the cellular changes that occur in the brain in response to developmental stressors may bring us closer to understanding the mechanisms that underlie these functional consequences. Other projects in this Center grant proposal are designed to explore stress-induced changes in the brain at various levels of analysis, from molecular to behavioral. This project will examine the impact of aversive experience during early life on the structure of the brain. The studies proposed here focus on the hippocampal region, an area that is sensitive to stress and has been implicated in psychopathologies, including depression and posttraumatic stress disorder. The hippocampal region undergoes extensive development during the postnatal period that may render this structure potentially vulnerable to environmental perturbations. In particular, the granule neuron population of the dentate gyms is formed predominantly during the postnatal period. In fact, the production of these cells extends well into adulthood in most mammals, from rodents to primates. Previous studies have shown that the production of these hippocampal neurons is suppressed by stress in adulthood. This proposal is designed to explore the consequences of prolonged early life stress on the development of the granule neuron population, the CA3 pyramidal neuron population and the mossy fiber connections between these two cell groups using the rodent and primate models provided by the cores (PI, Plotsky), (PI, Insel). Using a variety of histological methods, including BrdU labeling, 3H-thymidine autoradiography, immunocytochemistry, Golgi impregnation and neuroanatomical tract tracing, the impact of early life stress on the formation and maintenance of hippocampal neurons will be explored. These studies will contribute to the Center's overall purpose to gain a better understanding of the effects of early life stress on brain structure and function and, ultimately, to the development psychopathology.